Methyl iodide → 2-Fluoro-4-(methylsulfanyl)aniline

Participants

Reaction Conditions

Reaction Steps

A solution of the product of Example 26, Step A, 4-amino-3-fluorophenyl thiocyanate (500 mg, 2.97 mmol), in ethanol (7.5 mL) was added to a solution of sodium sulfide monohydrate (714 mg, 2.97 mmol) in water (1.5 mL) and the mixture heated at 50° C. for 2 hours. Methyl iodide (464 mg, 3.27 mmol) in ethanol (0.5 mL) was added and heating continued for a further 4 hours. The reaction mixture was then diluted with water (15 mL) and extracted with Et2O (4×5 mL). The combined Et2O extracts were washed with water (3×10 mL), saturated NaCl (10 mL), and dried (Na2SO4), followed by removal of the solvent under reduced pressure to afford a pale yellow oil. This material was purified by dry flash column chromatography on silica (5% Et2O/hexanes as eluant) to give 2-fluoro-4-methylthioaniline as a pale yellow oil (407 mg, 87%); 1H NMR (400 MHz, CDCl3) δ 7.01 (dd, J=11.3, 2.1 Hz, 1 H), 6.94 (ddd, J=8.2, 2.1, 0.9 Hz, 1 H), 6.71 (dd, J=9.3, 8.2 Hz, 1 H), 3.67 (br s, 2 H), 2.42 (s, 3 H). Step C: Preparation of 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]-benzoic acid

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